Stereoselective formal synthesis of aspergillide A

Article abstract of DOI:10.1016/j.tetlet.2010.06.013

The stereoselective formal synthesis of aspergillide A (1), a cytotoxic 14-membered macrolide, is disclosed. The key intermediate, a trisubstituted tetrahydropyran core is prepared by SmI₂-induced intramolecular reductive cyclization as well as

Full text of DOI:10.1016/j.tetlet.2010.06.013

Tetrahedron Letters 51 (2010) 4195–4198
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Tetrahedron Letters
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Stereoselective formal synthesis of aspergillide A
*
Gowravaram Sabitha , D. Vasudeva Reddy, A. Senkara Rao, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective formal synthesis of aspergillide A (1), a cytotoxic 14-membered macrolide, is dis-
Received 3 March 2010
Revised 28 May 2010
Accepted 3 June 2010
Available online 8 June 2010
closed. The key intermediate, a trisubstituted tetrahydropyran core is prepared by SmI2-induced intramo-
lecular reductive cyclization as well as by using sequential
a-aminooxylation, Horner–Wadsworth–
Emmons olefination, and followed by Oxa-Michael cyclization. Other notable transformations in the syn-
thesis include the use of Jacobsen’s hydrolytic kinetic resolution, esterification, ring-closing metathesis
(RCM), and cross-metathesis (CM) reactions.
Keywords:
14-Membered macrolide
Z-Isomer
Ó 2010 Elsevier Ltd. All rights reserved.
Cross-metathesis
RCM
SmI2
a-Aminooxylation
Oxa-Michael
Recently, three novel 14-membered macrolides, named asper-
epoxide 8, whereas the aldehyde 7 could be obtained from the
epoxide 9.
gillides A, B, and C (Fig. 1, 1–3) were isolated by Kusumi and co-
workers1 from marine-derived fungus Aspergillus ostianus strain
01F313, cultured in a 1/2PD medium containing bromine-modified
artificial sea-water. These compounds were shown to exhibit sig-
nificant cytotoxic activity against mouse lymphocytic leukemia
In route A (Scheme 2), our synthesis commenced from chiral
epoxide 8, prepared from 4-pentene-1-ol following the literature
procedure.6 Opening of epoxide7 8 using trimethylsulfonium io-
dide, n-BuLi in dry THF at ꢀ10 °C provided secondary allylic alco-
hol 10 in 75% yield. The plan for the diastereoselective
construction of 13 was based on SmI2 reductive cyclization8,9 of
aldehydes such as 6. To this end, the allylic alcohol 10 was con-
densed with methyl propiolate. This was achieved by slow addition
of methyl propiolate10 to compound 10 via syringe pump over 16 h
to deliver the intermediate 11 in 90% isolated yield. Next, deprotec-
tion of the THP ether 11 by using PTSA in MeOH released the pri-
mary alcohol 12, which was immediately oxidized using IBX in
DMSO/CH2Cl2 to provide aldehyde 6. As anticipated, the SmI2-med-
iated cyclization of 6 proceeded to give 13 with high diasterocon-
cells with an IC50 value of 2.1, 70, and 2.0 lg/mL, respectively.
The structures originally proposed for aspergillides A (1) and B
(2) were revised2 by X-ray crystallography studies and the struc-
ture for aspergillide C (3) was confirmed to be correct by perform-
ing its synthesis.3 Both their unique pharmaceutical profile and
challenging chemical architectures have attracted considerable
interest, leading to numerous attempts and several successful syn-
theses of 2 and 3,4 but the synthesis of 1 is rare5 so it has driven us
to take-up the synthesis of aspergillide A (1).
From a retrosynthetic perspective (Scheme 1), we planned that
the side chain installation onto trisubstituted tetrahydropyran core
4 would be the late stage reaction. Thus, the 14-membered
macrolide 1 can be achieved from two fragments, 4 and 5, via
esterification followed by a ring-closing metathesis reaction or
cross-metathesis reaction and Yamaguchi lactonization. The tri-
substituted tetrahydropyran core 4 was prepared by two different
routes using a SmI2-induced intramolecular reductive cyclization
13
14
O
O
H
O
O
H
O
O
H
9
1
O
O
O
7
3
H
H
H
or sequential a-aminooxylation followed by in situ Horner–Wads-
worth–Emmons olefination and Oxa-Michael reaction from 6 and
HO
HO
HO
4
7, respectively. The 6 in turn could be prepared from the known
Aspergillide C (3)
Aspergillide A (1)
revised structures
Aspergillide B (2)
* Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail addresses: gowravaramsr@yahoo.com, sabitha@iict.res.in (G. Sabitha).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.013

4196
G. Sabitha et al. / Tetrahedron Letters 51 (2010) 4195–4198
O
HO2C
+
1
HO
TBSO
5
4
route B
route A
aminooxylation, Horner-Wadsworth-
Emmons, oxa-Michael reactions
SmI2 reductive
cyclization
O
TBSO
O
O
MeO2C
THPO
OH
PMBO
OHC
OHC
9
8
6
7
Scheme 1. Retrosynthesis.
O
OH
b
MeO2C
RO
O
a
THPO
THPO
8
10
R = THP
R = H
11,
12,
c
O
O
e
d
MeO2C
MeO2C
OHC
RO
6
R = H
R = TBS
13,
14,
f
O
g
HO2C
TBSO
4
Scheme 2. Reagents and conditions: (a) trimethylsulfonium iodide, n-BuLi, THF, ꢀ10 °C, 4 h, 75%; (b) methyl propiolate, DMAP, CH3CN, rt, 16 h, 90%; (c) PTSA, MeOH, 0 °C to
rt, 12 h, 81%; (d) IBX (o-iodoxybenzoic acid), DMSO, CH2Cl2, 0 °C to rt, 1 h, 78%; (e) SmI2 (0.1 M solution) (3 equiv), MeOH (3 equiv), THF, 0 °C, 1 h, 92%; (f) TBSCl, imidazole,
CH2Cl2, 0 °C to rt, 20 h, 88%; (g) LiOH, MeOH/H2O (8:2), 0 °C to rt, 10 h, 78%.
11
trol. Thus treatment of 6 with 3 equiv of SmI2 in the presence of
3 equiv of dry MeOH in THF effected reductive cyclization to give
2,6-syn-2,3-anti-tetrahydropyran 13 in 92% yield as the single
product. The hydroxy group was protected as TBS ether 14 and
cleavage of the methyl ester furnished acid 4 in excellent yield.
Product 14 was thoroughly characterized with the help of 2-D
nuclear Overhauser effect spectroscopy (NOESY) and double quan-
tum filter correlation spectroscopy (DQF-COSY) experiments. JH2–
smooth Oxa-Michael cyclization under thermodynamic conditions
in one-pot provided exclusively the 2,6-syn-2,3-anti tetrahydropy-
ran 13 (70%). The hydroxy group was protected as TBS ether 14 and
cleavage of the methyl ester furnished acid 4 in excellent yield. The
analytical and optical rotation values of 13, 14, and 4 exactly
matched with those of 13, 14, and 4 synthesized by Scheme 2.
Now, the stage is set to the synthesis of 1 to fasten the desired
fragments 4 and the known alcohol 515 together to obtain the 14-
membered macrocycle 1 (Scheme 4). Thus, the esterification of
alcohol 5 with carboxylic acid 4 was carried out under Yamaguchi
conditions16 to produce compound 20 in 79% yield. This set the
stage for the macrocyclization by ring-closing metathesis.
Reaction of diene 20 with second or first generation Grubbs’
catalyst17 in refluxing dichloromethane or using Grubbs–Hoveyda
(G–H) catalyst in the presence of 1,4-benzoquinone18 also resulted
in the exclusive formation of Z-isomer 21 in 90% yield. Finally, the
(Z)-isomer 21 was subjected to desilylation under TBAF conditions
to give the macrocyclic core 22 (J = 10.5 Hz) in 85% yield. The struc-
ture of macrolactone 22 was fully characterized by 1H NMR, 13C
NMR, and mass spectral data.
In addition, the cross-metathesis of hydroxy acid 4 with alcohol
5 carried out in the presence of 10 mol% of Grubbs-II catalyst affor-
ded 23 in 15 min as a mixture of E/Z in a ratio of 9:1. The formation
of the product was confirmed by 1H NMR analysis and comparison
with the literature data.5a
It is noteworthy to mention that when our work was under pro-
gress, a note appeared5b on the synthesis of aspergillide A 1 indi-
cating similar results on RCM and cross-metathesis reactions. The
spectral and analytical (1H, 13C NMR, mass, IR, and optical rotation)
data of our synthetic materials 22 and 23 were in complete agree-
ment with those reported.5a,5b As per the literature, the macrolact-
onization of 23 proved to be a difficult task. Only in the case of
TBS-ether and MOM-ether the product was obtained in 30% and
20% yields, respectively, under Yamaguchi conditions.5a,5c The seco
0
H3 = 9.1 Hz, JH5–H6 = 12.2, and JH5 –H6 = 1.7 Hz suggest that the H-2
and H-6 are diaxially disposed with respect to each other, which
is further confirmed by exclusive, strong NOE cross-peaks between
H2 and H6. Hence R- and S-stereocenter for C2 and C3, respec-
tively. Further NOE correlation H2/H4 and H4/H6 is consistent with
the chair conformation for six-membered pyran ring. The mini-
mum energy structure is adequately supported by NMR data.
These data (Figs. 2 and 3) suggest that the structure of the newly
formed ring in 1412 is the desired 2,6-syn-2,3-anti tetrahydropyran.
In route B (Scheme 3), the synthesis of the key intermediate 13
started from the epoxy alcohol 9 (98% ee, measured by chiral HPLC)
prepared as reported in our Letter.13 The alcohol was treated with
TPP and I2 in Et2O/CH3CN (3:1) in the presence of imidazole to get
the 2,3-epoxy iodide 15 in good yield, which on refluxing in MeOH
with Zn yielded the allylic alcohol 16. The allylic alcohol was pro-
tected as TBS ether 17 followed by removal of PMB group that pro-
vided the primary alcohol 18, which on oxidation using IBX in
DMSO/CH2Cl2 afforded the aldehyde. The aldehyde without isola-
tion was subjected to the crucial MacMillan14
using nitrosobenzene and 20 mol % -proline in DMSO followed
by in situ Horner–Wadsworth–Emmons olefination with trimethyl
phosphonoacetate and Cs2CO3 as base to furnish -anilinoxy- ,b-
unsaturated ester 19a, which was further treated with Cu(OAc)2
in ethanol at room temperature to cleave the O–N bond providing
the ester 19 with high enantiopurity (dr, >95:<5). Exposure of com-
pound 19 to TBAF for 20 h effected a silyl group removal and a
a-aminooxylation
D
c
a

G. Sabitha et al. / Tetrahedron Letters 51 (2010) 4195–4198
4197
ppm
3.55
3.60
3.65
3.70
3.75
3.80
3.85
3.90
3.95
4.00
H2/H6
4.00
3.95
3.90
3.85
3.80
3.75
3.70
3.65
3.60
3.55 ppm
Figure 2. Expansion of the NOESY spectrum showing the characteristic NOE correlations.
H
H
H
H
H
H
H
O
MeO2C
TBSO
H
2
6
R
OTBS
O
MeO
H
3
14
O
R = TBS
Figure 3. Chemical structure and energy-minimized structure of 14.
OR
O
O
b
a
PMBO
c
PMBO
OH
PMBO
I
16
17
R = H
R = TBS
15
9
OTBS
OTBS
e, f
g
d
MeO2C
HO
ONHPh
18
19a
OTBS
O
O
h
j
HO2C
TBSO
MeO2C
RO
MeO2C
OH
19
4
13 R = H
14
i
R = TBS
Scheme 3. Reagents and conditions: (a) TPP, imidazole, iodine, Et2O/CH3CN (3:1), 0 °C, 1 h; (b) Zn, MeOH, reflux, 1 h, (92% overall from 9); (c) TBSCl, imidazole, CH2Cl2, 0 °C to
rt, 4 h, 96%; (d) DDQ, CH2Cl2/H2O (9:1), 0 °C, 1 h, 91%; (e) IBX (o-iodoxybenzoic acid), DMSO, CH2Cl2, 0 °C to rt, 10 h; (f) (i) PhNO, -proline, DMSO, rt, 15 min, (ii) trimethyl
D
phosphonoacetate, cesium carbonate, rt, 2 h (60% overall from 18); (g) Cu(OAc)2, EtOH, rt, overnight, 85%; (h) TBAF, THF, 20 h, rt, 70%; (i) TBSCl, Imidazole, CH2Cl2, 0 °C to rt,
20 h, 88%; (j) LiOH, MeOH/H2O (8:2), 0 °C to rt, 10 h, 78%.
acid bearing benzyl ether as per the report is not stable under any
macrolactonization conditions.5b Since the conversion of 22 and 23
to aspergillide A 1 has already been reported in the literature,5a,5b
the present sequence herein constitutes a formal synthesis of
aspergillide A 1.
In conclusion, a formal synthesis of the 14-membered macro-
lide, aspergillide A (1) has been demonstrated. This synthesis
features a key SmI2 reductive cyclization step and sequential
a-aminooxylation–Horner–Wadsworth–Emmons olefination and
oxa-Michael cyclization reactions to access the trisubstituted pyr-

4198
G. Sabitha et al. / Tetrahedron Letters 51 (2010) 4195–4198
12. Spectral data: methyl 2-((2R,3S,6R)-3-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-6-
vinyltetrahydro-2H-2 pyranyl)acetate (14): ½a D25
ꢁ
+24.3 (c 0.01 g/mL, CHCl3); 1H
OH
5
H
H
O
O
H
O
O
H
O
b
NMR: (CDCl3, 600 MHz): d 5.81 (ddd, J = 5.1, 10.7, 17.4 Hz, 1H), 5.20 (td, J = 1.6,
17.4 Hz, 1H), 5.06 (td, J = 1.6, 17.4 Hz, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.65 (dt,
J = 3.2, 9.1 Hz, 1H), 3.35 (ddd, J = 4.4, 9.1, 10.3 Hz, 1H), 2.82 (dd, J = 3.3, 15.2 Hz,
1H), 2.39 (dd, J = 9.2, 15.2 Hz, 1H), 2.02 (qd, J = 3.8, 12.6 Hz, 1H), 1.77 (qd,
J = 2.8, 12.6 Hz, 1H), 1.62–1.41 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H);
13C NMR (CDCl3, 75 MHz): 172.2, 138.3, 114.8, 79.0, 77.6, 70.6, 51.5, 37.9, 33.2,
30.9, 25.7, 17.8, ꢀ4.0, ꢀ4.8; IR (Neat): 3060, 2933, 2858, 1744, 1640, 1464,
HO2C
TBSO
H
O
O
a
H
4
TBSO
RO
d
20
21
22
R = TBS
R= H
OH
c
ref 5b
5
1437, 1342, 1194, 1095, 990,927, 897, 840, 775, 671 cmꢀ1
; LC–MS: 315
ref 5a
[M+H]+; HRMS: m/z [M+Na]+ calcd for C16H31O4Si: 315.1991; found: 315.1991.
13. Sabitha, G.; Bhaskar, V.; Yadagiri, K.; Yadav, J. S. Synth. Commun. 2007, 37,
2491–2500.
OH
H
HO2C
TBSO
1
O
14. (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696–3697;
(b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, C. W. C. J. Am. Chem. Soc.
2003, 125, 10808–10809; (c) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247;
(d) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293; (e) Zhong, G. Chem. Commun. 2004, 606–607.
15. Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1 2000, 2385–2394.
16. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
H
23
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to rt, 6 h, 79%; (b)
Ru-I, CH2Cl2, reflux, 2 h, 90%; (c) TBAF, THF, rt, overnight, 85%; (d) Ru-II, CH2Cl2,
reflux, 15 min, 42%.
17. (a) Fürstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.; Teply´, F.;
Aïssa, C.; Moulin, E.; Müller, O. J. Am. Chem. Soc. 2007, 129, 9150–9161; (b)
Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 20, 3127–3129.
18. Hong, S. H.; Sander’s D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127,
17160.
an core. Other salient features of the approach include the use of
ring-closing metathesis and cross-metathesis reactions. We believe
that this approach sets the stage not only for the total synthesis of
aspergillide A (1) but also entry to a diversity of analogues through
the installation of various side chains. Studies in this direction are
underway.
Selected spectral data: (3R)-6-(tetrahydro-2H-2-pyranyloxy)-1-hexen-3-ol (10):
½
a 2D5
ꢁ
ꢀ6.2 (c 0.01 g/mL, CHCl3); 1H NMR (CDCl3, 300 MHz): d 5.91–5.78 (m, 1H),
5.22 (d, J = 17.1 Hz, 1H), 5.07 (d, J = 10.3 Hz, 1H), 4.60–4.56 (m, 1H), 4.16–4.08
(m, 1H), 3.87–3.72 (m, 2H), 3.53–3.44 (m, 1H), 3.43–3.34 (m, 1H), 2.23 (br s,
1H, OH), 1.89–1.47 (m, 10H); 13C NMR (CDCl3, 75 MHz): 141.0, 114.4, 98.8,
72.7, 67.5, 62.2, 34.2, 30.5, 25.8, 25.3, 19.4; IR (Neat): 3430, 3060, 2941, 2866,
1640, 1442, 1352, 1266, 1200, 1123, 1071, 1027, 988, 913, 868, 810, 758,
669 cmꢀ1; ESIMS: m/z 223 [M+Na]+; HRMS: m/z [M+Na]+ calcd for C11H20O3Na:
223.1310; found: 223.1303.
Acknowledgment
D.V.R and A.S.R thank CSIR, New Delhi, for the award of
fellowships.
Methyl (E)-3-[(1R)-1-(3-hydroxypropyl)-2-propenyl]oxy-2-propenoate (12): ½a D25
ꢁ
ꢀ5.3 (c 0.009 g/mL, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.46 (d, J = 12.0 Hz,
1H), 5.82–5.69 (m, 1H), 5.32–5.19 (m, 3H), 4.39–4.31 (m, 1H), 3.70–3.61 (m,
5H), 1.85–1.54 (m, 4H); 13C NMR (CDCl3, 75 MHz): 168.4, 161.6, 136.2, 118.2,
97.6, 83.7, 62.3, 51.1, 31.2, 28.1 ; IR (Neat): 3431, 3055, 3020, 2947, 1705, 1635,
1438, 1334, 1292, 1199, 1139, 1054, 967, 900, 832, 754 cm-1; LC–MS: m/z 223
[M+Na]+; HRMS: m/z [M+Na]+ calcd for C10H16O4Na: 223.0946; found:
223.0940.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.013.
((2R,3R)-3,4-[(4-Methoxybenzyl)oxy]butyloxiran-2-yl)methanol (9): ½a D25
ꢁ
+11.1 (c
0.0135 g/mL, CHCl3); 1H NMR (CDCl3, 500 MHz): d 7.19 (d, J = 8.6 Hz, 2H), 6.82
(d, J = 8.6 Hz, 2H), 4.39 (s, 2H), 3.83 (dd, J = 1.9, 12.5, Hz, 1H), 3.79 (s, 3H), 3.57
(dd, J = 4.8, 12.5 Hz, 1H), 3.41 (t, J = 6.7 Hz, 2H), 2.91–2.67 (m, 1H), 2.86–2.82
(m, 1H), 1.66–1.46 (m, 6H); 13C NMR (CDCl3, 75 MHz): 159.0, 130.4, 129.1,
113.6, 72.4, 69.6, 61.6, 58.4, 55.8, 55.2, 31.2, 29.3, 22.6 ; IR: 3424, 2932, 2860,
1611, 1513, 1460, 1248, 1096, 1032, 822, 757 cmꢀ1; LC–MS: 289 [M+Na]+;
HRMS: m/z [M+Na]+ calcd for C15H22O4Na: 289.1415; found: 289.1407.
References and notes
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2008, 10, 225–228.
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(5R)-5-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-6-hepten-1-ol (18): ½ ꢁ ꢀ5.6 (c
a 2D5
4. Syntheses of aspergillide B and C: (a) Hande, S. M.; Uenishi, J. Tetrahedron Lett.
2009, 50, 189–192; (b) Liu, J.; Xu, K.; He, J.-M.; Zhang, L.; Pan, X.-F.; She, X.-G. J.
Org. Chem. 2009, 74, 5063–5066; (c) Nagasawa, T.; Kuwahara, S. Biosci.
0.0115 g/mL, CHCl3); 1H NMR (CDCl3, 300 MHz): d 5.82–5.69 (m, 1H), 5.15–
5.07 (m, 1H), 5.03–4.98 (m, 1H), 4.17–4.03 (m, 1H), 3.61 (t, J = 6.7 Hz, 2H),
1.61–1.30 (m, 6H), 0.89 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3,
75 MHz): 141.5, 113.6, 73.7, 62.5, 37.6, 32.6, 25.8, 21.2, 18.2, ꢀ4.4, ꢀ4.9 ; IR
(Neat): 3351, 3080, 2934, 2859, 1643, 1466, 1418, 1253, 1087, 1034, 924, 837,
775, 676 cmꢀ1; LC–MS: 245 [M+H]+; HRMS: m/z [M+H]+ calcd for C13H29O2Si:
245.1936; found: 245.1938.
´
Biotechnol. Biochem. 2009, 73, 1893–1894; (d) Dıaz-Oltra, S.; Angulo-Pachon,
C. A.; Kneeteman, M. N.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2009,
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´
5. (a) Nagasawa, T.; Kuwahara, S. Tetrahedron Lett. 2010, 51, 875–877; (b) Dıaz-
Oltra, S.; Angulo-Pachon, C. A.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem.
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Methyl (2E,4S,7R)-7-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4-hydroxy-2,8-nonadienoate
(19): ½a 2D5
ꢁ
ꢀ28.4 (c 0.0225 g/mL, CHCl3); 1H NMR (CDCl3, 300 MHz): d 6.94 (dd,
J = 4.5, 15.8 Hz, 1H), 6.07 (dd, J = 2.2, 15.8 Hz, 1H), 5.86–5.72 (m, 1H), 5.21–5.05
(m, 2H), 4.35–4.19 (m, 2H), 3.75 (s, 3H), 2.80 (br s, 1H, OH), 1.75–1.55 (m, 4H),
0.91 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 75 MHz): 167.1, 150.4,
140.5, 119.7, 114.5, 73.5, 71.0, 51.5, 33.8, 31.8, 25.8, 18.2, ꢀ4.4, ꢀ4.9 ; IR
(Neat): 3446, 2925, 2855, 1726, 1656, 1462, 1258, 1170, 1077, 923, 836,
775 cmꢀ1; LC–MS: 337 [M+Na]+; HRMS: m/z [M+Na]+ calcd for C16H30O4NaSi:
337.1811; found: 337.1799.
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7. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Legall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
8. (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40,
2811; (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999, 1, 1099; (c) Matsuo,
G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999, 40, 8859; (d) Matsuo, G.;
Kadohama, H.; Nakata, T. Chem. Lett. 2002, 148–149; (e) Hori, N.; Matsukura,
H.; Matsuo, G.; Nakata, T. Tetrahedron 2002, 58, 1853.
9. Selected papers: (a) Fuwa, H.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2006, 128,
9648; (b) Fuwa, H.; Kakinuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc.
2002, 124, 14983; (c) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.;
Satake, M.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 11893; (d) Nagumo, Y.;
Oguri, H.; Shindo, Y.; Sasaki, S.; Oishi, T.; Hirama, M.; Tomioka, Y.; Mizugaki,
M.; Tsumuraya, T. Bioorg. Med. Chem. Lett. 2001, 11, 2037; (e) Matsuo, G.;
Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T. J. Am. Chem. Soc. 2004, 126,
14374; (f) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int. Ed. 2002, 41,
4751.
(1R,5S,11R,14S)-14-Hydroxy-5-methyl-4,15-dioxabicyclo-[9.3.1]pentadec-9(Z)-
en-3-one (22): ½a D25
ꢁ
+38.2 (c 0.006 g/mL, CHCl3), lit5b a 2D5
½ ꢁ +42.9 (c 0.077,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 5.64–5.53 (m, 1H), 5.16 (dd, J = 2.2,
10.5 Hz, 1H), 5.06–4.93 (m, 1H), 4.08–4.00 (m, 1H), 3.56–3.47 (m, 1H), 3.35–
3.25 (m, 1H), 2.81 (dd, J = 2.2, 11.3 Hz, 1H), 2.30 (t, J = 11.3 Hz, 1H), 2.32–2.09
(m, 2H), 2.00 (br s, OH) 1.83–1.74 (m, 1H), 1.72–1.40 (m, 7H), 1.25 (d, J = 6.0 Hz,
3H); 13C NMR (CDCl3, 75 MHz): 173.3, 135.7, 128.0, 81.5, 74.8, 70.1, 69.8. 39.0,
34.4, 33.6, 31.9, 28.0, 25.7, 20.9; IR (Neat): 3431, 3020, 2923, 2854, 1725, 1655,
1459, 1371, 1275, 1183, 1133, 1075, 969, 758, 678 cmꢀ1; LC–MS: 277 [M+Na]+;
HRMS: m/z [M+Na]+ calcd for C14H22O4Na: 277.1415; found: 277.1427.
2-(2R,3S,6R)-3-hydroxy-6-[(E,6S)-6-hydroxy-1-heptenyl]tetrahydro-2H-2-pyranyl
acetic acid (23): ½a D25
ꢁ
+48.4 (c 0.005 g/mL, CHCl3), 1H NMR (CDCl3, 500 MHz): d
5.67–5.52 (m, 1H), 5.39 (dd, J = 5.2, 15.6 Hz, 1H), 3.85–3.71 (m, 2H), 3.60–3.53
(m, 1H), 3.36–3.28 (m, 1H), 2.77 (dd, J = 3.1, 14.5 Hz, 1H), 2.39–2.33 (m, 1H),
2.15–1.95 (m, 4H), 1.75–1.60 (m, 1H), 1.57–1.34 (m, 5H), 1.16 (d, J = 6.2 Hz,
3H), 0.88 (s, 9H), 0.06 (s, 6H); LC–MS: 409 [M+Na]+; HRMS: m/z [M+Na]+ calcd
for C20H38O5NaSi: 409.5902; found: 409.5893.
10. (a) Winterfeldt, E. Chem. Ber. 1964, 97, 1952–1958; (b) Winterfeldt, E.; Preuss,
H. Chem. Ber. 1966, 99, 450–458.
11. (a) Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5; (b) Girard, P.;
Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693; (c) Kagan, B. H. New J.
Chem. 1990, 14, 453.